Reduction of ketones



Patented May 23, 1950 "White Laboratories, Inc.", Newarlg, N. ;I., a Q9 .poration of New Jersey Na l awit Application September ;1'9 ,;l9 1 6.

This invention relates to a method for thereduction of ketones, particularly-to a method for the dimolecular reduction thereof to form pinacolsi This application is a continuation inpart of application Serial No. 649,137, filed January 7, 1946, now U. -S. Patent No.'2,474, 2 16.

The dimolecular reduction of ketones to pinacols is eiffected by submitting the ketone to the action of nascenthydrogen. The reduction has heretofore usually been 'efiected with metals in aqueous acid solutions, electrolytically or with an amalgam of sodium, magnesiuin or aluminum in an anhydrous solvent for the ketone capable oi acting as ahydrogen donor. Thesemethod s each possess certain inherent difiiculti es. Reduction with a metal and aqueous acid or electrolytically invariably leads to low yields and, particularly in the first instance, to the formation of secondary alcohols. The use of an aluminum ormagnesiu 'n amalgam, although leading to higher yields, re-

sults in the formation offl miiitlll' containing a voluminous precipitate of magnesiumbr alumi Hum h d x rom iC t s fl fiiwltio a or o er i e se ara e th ila lr The s e aratienandusaq so iu ma eamiis cificu t car 0.1 3 u t t hi h reacti e natur and its. .q inmerq al use is mmaterial- Th r ilu ha e fillli li fi i iqi fi fifliPl re uen y has b en a umi um amal amamalgam, however, is difficult to prepare in a ei .ea inasatisi to a t v i and th rsqll i aa en .Q he amalg m llllder b st qond iQas sna s rah sl wirhepiepaia enef alum.-. amalgam in large quantities is especially difiiicult due to the critical conditions which must be maintained during its preparation. Inasmuch as the pinacols are intermediates in the preparation of many valuable products, it is apparent thatany improvement in the-method of their manufacture is desirable.

It is thereforean object of-the'pre sent' invention to provide a method-for the dimolecul arreduction of ketones to' formpinacols.

te ad iqeal ob ect 1st? .pra iee when?! th p eparati n .Qia iea qlin .subiectt the ifficult eso e h e r knew-methodsadditional ob ec i to p ovid a ethod the preparation. of a pi-na col Joy "the dirnolecular ed cti o a .lsei i whe ei the pina i a b sepa a ed .Q0nv nient1yandin,- hi -hvield from the reaction mixture.

An -.additional object isto provide anew reducing agent for the dimolecular-meduction of -ketone toform pinacols.

Other objects will become apparent as the description proceeds;

According to. theipresent invention, the fore..- gcing and related obiectsare accomplishedlmadily and. economically by reducing a ketone with an alloy ofan alkali metal and lead ina solvent for the ketone capable of. serving as aihydrogendonor and maintaining in I the-mixture an effective .6011? centration .of ions of .an .alkaline' earth metal. The term falkalineiearth metal? Iasused herein refers :to the -inetals magnesium, .calcium, barium and strontiumi V 'llhe method of.,.the invention. offers certain ad,- vantages' not. .possib'lef to. obtain lwhen Lusingv .the heretofore Zknowln reducing agents for .ketones or when using a: sodium-lead alloy in the. absence of alkaline earth metal ions. Inaddition tothe formation 'of pure spinaools. in' higherlyields than heretoiore obtainable, the reaction mixture is of such a" nature that the pinacol mayibe recovered therefrom .v'vithease. Due to .theTsolubility ofith salts of the alkali metals and .to the solubility of many of the-salts'lof thealkalin earth metals, reagents "maybe chosen, according to. a preferred modification of 'theinventiomto avoid the forma; tion of undesired insolublemetal salts inlthe reaction mixture. The metallic lead remaining of separation.

The alkaline earth metal ions maybe intro.- ducedi-nto the reactionmixture in.a number of. ways. The preferred way consists in addingan ion-producing salt or compoundof an alkaline earthmetal tothe-mixture Iorlsolutioncontaining the ketone hich-is to be reduced. Ohlya very low concentration L of alkaline earth .metal @ions in'th solutionis requiredand itlappears thatzth effect is somewhat catalytic in nature. -The,pree encaof. amoderately high concentra iqnm alk line earth metal ions-.1 1 il h itm ll'b i 1. 9 13%?" lievedta be dehtefieus- .elte n tiie ran kalin iearth m ta a -lie iacmi q ate ihe 3 d the mixture settles readily and offers no promem a hleia hieiiaeeai sedwifi f ntir see 9' igu f v 'Ijhereduction may be carried out in acid,neu tral or alkaline solutibn using warajaqeeaus alcohol orentirely organic sowents provided only 7 that a hydrogen donor b'e present and that the atoms? nomic reasons and the invention will be described with particular respect thereto.

Sodium-lead alloys are prepared conveniently by melting sodium and lead together in the absence of air. The product is a brittle solid at ordinary temperatures and is preferably ground to a powder prior to being employed in reducing a ketone. It is conveniently preserved under hydrocarbon liquids or in an atmosphere of inert I gases. In carrying out the reduction of a ketone, an alloy is used containing from about 5 per cent, or somewhat lower, to about 40 per cent, or somewhat higher, of alkali metal. Best results have been obtained using an alloy containing from about 8 per cent to about 15 per cent of sodium or other alkali metal.

When it is desired to use a sodium-lead alloy containing an alkaline earth metal, the alloy may be prepared as described previously and the alkaline earth metal incorporated prior to heating. In certain instances, it is desirable to premelt the alkaline earth metal with the lead prior to the formation of the sodium-lead alloy.

The method of the invention is applicable to the 'dimolecular reduction of a wide variety of ketones including dialkyl ketones, alkyl aryl ketones, diaryl ketones and alkyl aralkyl ketones 'as well as substitution derivatives thereof wherein the substituent is non-reactive under the reaction conditions. Ketones which are reduced successfully to pinacols utilizing the method of the invention include methyl ethyl ketone, propyl butyl ketone, hexyl ethyl ketone, methoxybutyl propyl ketone, benzophenone, methyl phenyl ketone, methoxyphenyl propyl ketone, hydroxyphenyl propyl ketone, methoxyphenyl butyl ketone, chlorophenyl propyl ketone, -p hydroxypropiophenone, p methoxypropiophenone, methyl benzyl ketone, methyl chloro- .benzyl ketone, ethyl tolyl ketone, p-chloropropiophenone, p-methoxybutyrophenone, butyl methoxybenzyl ketone, chlorobenzophenone, bromobenzophenone, and many others. A preferred embodiment of the invention relates to the reduction of alkyl aryl ketones, alkyl aralykyl ketones and their substitution products wherein the substituent group is nonreactive under the reaction conditions. Water-soluble salts of 'ketones containing a salt-forming radical may also be used.

In carrying out the reduction of a ketone according to the preferred modification, the ketone, solvent and alkaline earth metal salt are stirred "together and the finely divided alloy added slowly. In case an alloy is used containing an alkaline earth metal, the addition of the soluble alkaline earth metal salt is, of course, unnecessary. Satisfactory'results have been obtained by dissolving the ketone in alcohol, a mixture of glacial acetic acid and aqueous alcohol, aqueous alcohol, or water according to its solubility in such solvents. Water-insoluble ketones containing a functional group such as an hydroxy, carboxyl, or sulfo group, capable of forming a water-soluble salt, such as p-hydroxypropiophenone, may be con- :verted to the salt and the reduction then carmixture, and other factors.

ried out in water and such variation is included within the scope of the invention.

Mixtures of alcohols, acids and other substances capable of serving as hydrogen donors with non-polar liquids such as benzene may be used, if desired, although such procedure is not usually desirable due to the tendency of the nonpolar liquid to precipitate sodium salts during the course of the reaction. A hydrogen donor, as herein referred to, is any substance, liquid under the reaction conditions, capable of reacting with a sodium-lead alloy under such reaction conditions to furnish nascent hydrogen.

Although the reaction proceeds satisfactorily at low temperatures, e. g., at from 0 to 40 C., it may be carried out at temperatures as high as C., or even higher. The reduction is usually complete in from a few minutes to several hours, depending upon the quantity of material being reduced, the temperature, the proportion of ketone to alloy, the degree of agitation of the The reduction may be completed in form one to four hours. Somewhat more than the theoretical proportion of sodium, i. e., from 2.25 to 4.0 gram atoms of sodium for each mol of ketone, is usually employed to facilitate reduction of all of the ketone. The reaction mixture is preferably agitated vigorously throughout the reduction period.

Following the completion of the reduction, the metallic lead in the mixture is allowed to settle and removed by filtering or decanting and the liquid portion of the reaction mixture worked up in any convenient way to recover the pinacol therefrom. When the reduction is carried out in aqueous solution, the pinacol is conveniently recovered by extraction procedures or, in the a suitable solvent. Other ways of separating and purifying the pinacol will be apparent to those familiar with the art and the invention is not limited as to such methods of recovery or purification.

Certain advantages of the invention are apparent from the following examples which are given by way of illustration only and are not to be construed as limiting.

Example 1 The lead residue was washed with suflicient water to bring the total volume of decanted liquid and washings up to 450 milliliters. Most of the excess sodium hydroxide in the solution was neutralized by adding 25 milliliters of acetic acid and the solution heated to about'60 C. and filtered. The

clear filtrate was cooledito 15 (land acidified containing 70 per cent lead and 30 per cent sodium was added over a period 01' one hour. After stirring ior another hour, the lead was allowed to settle, the supernatant liquid was decanted and the lead residue washed with suithcient water to bring the total volume of decanted liquid and washings up to 350 milliliters. Most oi the excess sodium hydroxide was neutraiized by adding 50 milliliters oi acetic acid and the solution was heated to 60 C. and filtered. The clear filtrate was cooled to 15 C. and acidified slowly to litmus with acetic acid. The crude pinacol was recovered by filtering and washed with water and then dried at 50 C. The yield oi crude 3,4-bisip-hydroxyphenyl) -3,4-hexanediol so obtained weighed 26.5 grams. After washing thoroughly with glacial acetic acid, the dried product weighed 18.6 grams and melted at 160 to 181 C. Upon analysis, the washed and dried product was found to contain 37.4 per cent of unchanged p-hydroxypropiophenone. The actual yield of pinacol was therefore 11.? grams.

Example 8 Thirty grame of p-hydroxypropiophenone was reduced with an alloy containing 70 per cent lead and 30 per cent sodium by the method of example 7, except that the calcium chloride was omitted from the reaction mixture. The yield of 3,4-bis- (p-hydroxyphenyi) 3,4 hexanediol, based on phenone-free product, was 5.1 grams.

Example 9 A solution consisting of 21.2 grams of p-rnethoxy-butyrophenone and 6 grams of anhydrous calcium chloride in 600 milliliters of alcohol was agitated rapidly at 15 to 20 C. and 200 grams of a powdered alloy containing 90 per cent lead and 10 per cent sodium was added over a period of 45 minutes. The mixture was stirred for an additional 20 minutes at 20 to 25 C., the lead allowed to settle and the supernatant liquid decanted. The alcohol was distilled in vacuo from the decanted liquid. The oily residue remaining was washed with water to remove alkali, dissolved in ether and the solution dried with sodium sulfate. The dry ethereal solution was warmed gently to distill ether and the last traces of ether then removed in vacuo. The residue consisted of 62.5 grams of a clear, pale yellow, viscous oil which was found to be free of unchanged p-methoxybutyrophenone and which, upon analysis. was found to contain 94 per cent of 4,5bis-(p-methoxyphenyl) 4,5 g octanediol. The product was a mixture of meso and racemic isomers which were later separated in crystalline form by crystallization from a mixture of benzene and petroleum ether.

Example 10 One hundred grams of a finely divided sodiumlead alloy containing 10 per cent of sodium, and no alkaline earth metal, was added at 20 to 25 C. during one-half hour to a refluxing solution of 35.6 grams of p-methoxybutyrophenone in 300 milliliters of 80 per cent alcohol. The mixture was then refluxed for three hours and the alcoholic solution decanted from the lead residue. The alcohol was distilled from the solution and the residue crystallized from a mixture of henzene and petroleum ether. A 60 per cent yield of crystalline 4,5-bis-(p-methoxyphenyl)-4,5- octanediol was obtained. This comprised a mixture of the meso forms meltingat 144 to 145" Example 11 A solution containing 100 grams of propiophenone and 12 grams of crystallized magnesium sulfate in 960 milliliters of per cent alcohol was agitated rapidly at 20 to 35 C. and 500 grams of apowdered alloy containing per cent lead and 10 per cent sodium was added over a period of 45 minutes. The mixture was stirred for an additional 15 minutes and the lead allowed to settle. The clear, supernatant liquid was decanted and neutralized carefully with acetic acid and filtered. The alcohol was removed from the mixture by distillation in vacuo and the almost colorless, viscous residue washed with water to remove sodium acetate. The washed product was dried at 80 C. in vacuo. The dry product, which weighed 98 grams, was an almost colorless, very viscous oil. Upon analysis, the oil was found to contain 92 per cent of a mixture of meso and racemic 3,4-diphenyl-3,4- hexanediol. The meso form was isolated by crystallization from the alcohol and then melted at 137 to 137.5 C.

I claim:

, 1. The method for producing a pinacol which comprises contacting a ketone with an alkali metal-lead alloy under the influence of ions of an alkaline earth metal.

2. The method of claim 1, wherein the ketone is an aralkyl alkyl ketone.

. 3. The method of claim 1, wherein the ketone is an aralkyl aryl ketone.

4. The method of claim 1, wherein the ketone is water-soluble.

5. The method of claim 1 wherein the alkali metal-lead alloy is a sodium-lead alloy.

6. The method of claim 1 wherein the alkali metal-lead alloy contains from about 5 to about 40 per cent of alkali metal.

7. The method of claim 1 wherein the alkaline earth metal is calcium.

8. The method of claim 1 wherein the ketone is an alkyl aryl ketone.

9. The method of claim 1 wherein the ketone is p-hydroxypropiophenone.

10. The method of claim 1 wherein the ketone is p-methoxypropiophenone.

. 11. The method of claim 1 wherein the ketone is p-chloropropiophenone.

12. The method of claim 1 wherein the ketone is p-methoxybutyrophenone.

13. The method for producing a 'pinacol which includes contacting a mixture comprising a ketone, 3, hydrogen donor and an alkaline earth metal ion with an alkali metal-lead alloy.

- 14. The method of claim 13 wherein the hydrogen donor is water.

15. The method of claim 13 wherein the hydrogen donor is an organic liquid.

16. The method of claim 13 wherein the hydrogen donor is a solvent for the ketone and the alkaline earth metal ion.

17. The method for producing a pinacol which includes: contacting a ketone in a solution comprising a hydrogen donor and an alkaline earth metal ion with an alkali metal-lead alloy; and separating a pinacol from the reaction mixture.

18. The method for producing a pinacol which includes: contacting a solution comprising a hydrogen donor and a ketone with an alkali metalleadalloy containing a minor proportion of an alkaline earth metal to effect conversion of at least a part of the alkaline earth metal to alkaline earth metal ions; continuing the contacting of the ketone with the alkali metal-lead alloy under the influence of the so-formed ions; and separating a pinacol from the reaction mixture.

PHILIP J. BREIVOGEL.

REFERENCES CITED The following references are of record in the file of this patent:

10 UNITED STATES PATENTS Number Name Date 2,349,770 Tendick May 23. 1944 2,421,401 Adler et a1 June 3, 1947 OTHER REFERENCES Goldach, Helv. Chim. Acta, vol. 14, 1436-44 

1. THE METHOD FOR PRODUCING A PINACOL WHICH COMPRISES CONTACTING A KETNE WITH AN ALKALI METAL-LEAD ALLOY UNDER THE INFLUENCE OF IONS OF AN ALKALINE EARTH METAL. 